title: mTOR inactivation by ROS-JNK-p53 pathway plays an essential role in psedolaric acid B induced autophagy-dependent senescence in murine fibrosarcoma L929 cells.
abstract: Pseudolaric acid B (PAB), the primary biologically active compound isolated from the root bark of P. kaempferi Gordon, has been reported to exhibit anti-tumor effect primarily via cell cycle arrest and apoptosis. Our previous study demonstrated that PAB triggered mitotic catastrophe in L929 cells. In addition, a small percentage of the cells undergoing mitotic catastrophe displayed an apoptotic phenotype. Therefore, we continued to investigate the fate of the other cells. The results indicated that PAB induced senescence through p19-p53-p21 and p16-Rb pathways in L929 cells. PAB also triggered autophagy via inhibiting Akt-mammalian target of rapamycin (mTOR) activity in L929 cells. In addition, autophagy was demonstrated to reinforce senescence through regulating the senescence pathways. Thus, we focused on the detailed molecular mechanisms whereby autophagy promoted senescence. Reactive oxygen species (ROS) plays an important in autophagy and senescence. We found that PAB triggered a ROS-JNK-p53 positive feedback loop and this feedback loop played a crucial role in autophagy via repressing the activation of mTOR. Furthermore, ROS-JNK-p53 positive feedback loop was demonstrated to regulate senescence. Tuberous sclerosis proteins1 and 2, also known as TSC1 and TSC2, form a protein-complex. TSC1/TSC2 heterodimer is a downstream target of growth factor-phosphoinositide 3-kinase-Akt signaling which negatively regulates mTOR activity. Activation of mTOR by insulin or inhibition of endogenous TSC2 levels by siRNA obviously delayed PAB-induced senescence. In conclusion, mTOR inactivation by ROS-JNK-p53 pathway played an important role in autophagy-dependent senescence in PAB-treated L929 cells.
authors.affiliation: China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, China.
authors.forename: Min
authors.initials: M
authors.lastname: Qi
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhou
authors.forename: Simiao
authors.initials: S
authors.lastname: Fan
authors.forename: Zhao
authors.initials: Z
authors.lastname: Li
authors.forename: Guodong
authors.initials: G
authors.lastname: Yao
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tashiro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Onodera
authors.forename: Mingyu
authors.initials: M
authors.lastname: Xia
authors.forename: Takashi
authors.initials: T
authors.lastname: Ikejima
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D025461:Feedback, Physiological / Q000187:drug effects; D005354:Fibrosarcoma / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D004224:Diterpenes; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C058391:pseudolaric acid B; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Autophagy; Pseudolaric acid B; ROS-JNK-p53 pathway; Senescence; mTOR inactivation